Medicaments

ABSTRACT

This invention relates to aerosol formulations of use for the administration of medicaments by inhalation, in particular a pharmaceutical aerosol formulation which comprises particulate salbutamol and physiologically acceptable salts and solvates thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, which formulation is substantially free of surfactant. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as defined is also described.

[0001] This invention relates to aerosol formulations of use for theadministration of medicaments by inhalation.

[0002] The use of aerosols to administer medicaments has been known forseveral decades. Such aerosols generally comprise the medicament, one ormore chlorofluorocarbon propellants and either a surfactant or asolvent, such as ethanol. The most commonly used aerosol propellants formedicaments have been propellant 11 (CCl₃F) and/or propellant 114(CF₂ClCF₂Cl) with propellant 12 (CCl₂F₂). However these propellants arenow believed to provoke the degradation of stratospheric ozone and thereis thus a need to provide aerosol formulations for medicaments whichemploy so called “ozone-friendly” propellants.

[0003] A class of propellants which are believed to have minimalozone-depleting effects in comparison to conventionalchlorofluorocarbons comprise fluorocarbons and hydrogen-containingchlorofluorocarbons and a number of medicinal aerosol formulations usingsuch propellant systems are disclosed in, for example, EP 0372777,WO91/04011, WO91/11173, WO91/11495 and WO91/14422. These applicationsare all concerned with the preparation of pressurised aerosols for theadministration of medicaments and seek to overcome the problemsassociated with the use of the new class of propellants, in particularthe problems of stability associated with the pharmaceuticalformulations prepared. The applications all propose the addition of oneor more of adjuvants such as alcohols, alkanes, dimethyl ether,surfactants (including fluorinated and non-fluorinated surfactants,carboxylic acids, polyethoxylates etc) and even conventionalchlorofluorocarbon propellants in small amounts intended to minimisepotential ozone damage.

[0004] Thus, for example EP 0372777 requires the use of1,1,1,2-tetrafluoroethane in combination with both a cosolvent havinggreater polarity than 1,1,1,2-tetrafluoroethane (e.g. an alcohol or alower alkane) and a surfactant in order to achieve a stable formulationof a medicament powder. In particular it is noted in the specificationat page 3, line 7 that “it has been found that the use of propellant 134a(1,1,1,2-tetrafluoroethane) and drug as a binary mixture or incombination with a conventional surfactant such as sorbitan trioleatedoes not provide formulations having suitable properties for use withpressurised inhalers”. Surfactants are generally recognised by thoseskilled in the art to be essential components of aerosol formulations,required not only to reduce aggregation of the medicament but also tolubricate the valve employed, thereby ensuring consistentreproducibility of valve actuation and accuracy of dose dispensed.Whilst WO91/11173, WO91/11495 and WO91/14422 are concerned withformulations comprising an admixture of drug and surfactant, WO91/04011discloses medicinal aerosol formulations in which the particulatemedicaments are pre-coated with surfactant prior to dispersal in1,1,1,2-tetrafluoroethane.

[0005] We have now surprisingly found that, in contradistinction tothese teachings, it is in fact possible to obtain satisfactorydispersions of certain medicaments in fluorocarbon orhydrogen-containing chlorofluorocarbon propellants such as1,1,1,2-tetrafluoroethane without recourse to the use of any surfactantor cosolvent in the composition, or the necessity to pre-treat themedicament prior to dispersal in the propellant. More particularly,satisfactory dispersions may be formed where the medicament is selectedfrom salmeterol, salbutamol, fluticasone propionate, beclomethasonedipropionate and physiologically acceptable salts and solvates thereof.

[0006] There is thus provided in one aspect of the invention apharmaceutical aerosol formulation which comprises particulatemedicament selected from the group consisting of salmeterol, salbutamol,fluticasone propionate, beclomethasone dipropionate and physiologicallyacceptable salts and solvates (for example hydrates) thereof and afluorocarbon or hydrogen-containing chlorofluorocarbon propellant, whichformulation is substantially free of surfactant. By “substantially freeof surfactant” is meant formulations which contain no significantamounts of surfactant, for example less than 0.0001% by weight of themedicament.

[0007] In an alternative embodiment the present invention provides apharmaceutical aerosol formulation as hereinbefore defined with theproviso that when said formulation consists essentially of salbutamoland 1,1,1,2-tetrafluoroethane in a weight ratio of 0.05:18, saidsalbutamol is present in the form of a physiologically acceptable salt.

[0008] The particle size of the particulate (e.g. micronised) medicamentshould be such as to permit inhalation of substantially all of themedicament into the lungs upon administration of the aerosol formulationand will thus be less than 100 microns, desirably less than 20 microns,and preferably in the range 1-10 microns, e.g. 1-5 microns.

[0009] Suitable pharmaceutically acceptable salts of the medicaments ofuse in the formulations of the present invention include acid additionsalts such as for example sulphates, hydrochlorides and xinafoates(1-hydroxy-2-naphthoate), amine salts or alkali metal salts (e.g.sodium). Salmeterol will preferably be in the form of its xinafoate saltand salbutamol will preferably be in the form of its sulphate salt.

[0010] The final aerosol formulation desirably contains 0.005-10% w/w,preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

[0011] The propellants for use in the invention may be any fluorocarbonor hydrogen-containing chlorofluorocarbon or mixtures thereof having asufficient vapour pressure to render them effective as propellants.Preferably the propellant will be a non-solvent for the medicament.Suitable propellants include, for example, C₁₋₄hydrogen-containingchlorofluorocarbons such as CH₂ClF, CClF₂CHClF, CF₃CHClF, CHF₂CClF₂,CHClFCHF₂, CF₃CH₂Cl and CClF₂CH₃; C₁₋₄hydrogen-containing fluorocarbonssuch as CHF₂CHF₂, CF₃CH₂F, CHF₂CH₃ and CF₃CHFCF₃; and perfluorocarbonssuch as CF₃CF₃ and CF₃CF₂CF₃.

[0012] Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of the aboveidentified compounds or mixtures, preferably binary mixtures, with otherfluorocarbons or hydrogen-containing chlorofluorocarbons for exampleCHClF₂, CH₂F₂ and CF₃CH₃. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellant.Particularly preferred as propellants are C₁₋₄hydrogen-containingfluorocarbons such as 1,1,1,2-tetrafluoroethane(CF₃CH₂F) and1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃CHFCF₃).

[0013] It is desirable that the formulations of the invention contain nocomponents which may provoke the degradation of stratospheric ozone. Inparticular it is desirable that the formulations are substantially freeof chlorofluorocarbons such as CCl₃F, CCl₂F₂ and CF₃CCl₃.

[0014] The propellant may additionally contain a volatile adjuvant suchas a saturated hydrocarbon for example propane, n-butane, isobutane,pentane and isopentane or a dialkyl ether for example dimethyl ether. Ingeneral, up to 50% w/w of the propellant may comprise a volatilehydrocarbon, for example 1 to 30% w/w. However, formulations which aresubstantially free of volatile adjuvants are preferred.

[0015] It is further desirable that the formulations of the inventionare substantially free of liquid components of higher polarity than thepropellant employed. Polarity may be determined for example, by themethod described in European Patent Application Publication No 0327777.In particular formulations which are substantially free of alcohols suchas ethanol are preferable. As used herein “substantially free” meansless than 1% w/w based upon the fluorocarbon or hydrogen-containingchlorofluorocarbon, in particular less than 0.5% for example 0.1% orless.

[0016] A particularly preferred embodiment of the invention provides apharmaceutical aerosol formulation consisting essentially of one or moreparticulate medicament selected from the group consisting of salmeterol,salbutamol, fluticasone propionate, beclomethasone dipropionate andphysiologically acceptable salts and solvates thereof, and one or morefluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

[0017] It will be appreciated by those skilled in the art that theaerosol formulations according to the invention may, if desired, containa combination of two or more active ingredients. Aerosol compositionscontaining two active ingredients (in a conventional propellant system)are known, for example, for the treatment of respiratory disorders suchas asthma. Accordingly the present invention further provides aerosolformulations in accordance with the invention which contain two or moreparticulate medicaments. Medicaments may be selected from suitablecombinations of the medicaments mentioned hereinbefore or may beselected from any other suitable drug useful in inhalation therapy andwhich may be presented in a form which is substantially completelyinsoluble in the selected propellant. Appropriate medicaments may thusbe selected from, for example, analgesics, e.g. codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen ornedocromil; antiinfectives e.g. cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines and pentamidine;antihistamines, e.g. methapyrilene; anti-inflammatories, e.g.flunisolide, budesonide, tipredane or triamcinolone acetonide;antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine,adrenaline, fenoterol, formoterol,. isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol,terbutaline, isoetharine, tulobuterol, orciprenaline, or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol;.diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimise the activity. and/or stability of the medicament and/or tominimise the solubility of the medicament in the propellant.

[0018] Particularly preferred aerosol formulations contain salbutamol(e.g. as the free base or the sulphate salt) or salmeterol (e.g. as thexinafoate salt) in combination with an antiinflammatory steroid such asa beclomethasone ester (e.g. the diproprionate) or a fluticasone ester(e.g. the propionate) or an antiallergic such as cromoglycate (e.g. thesodium salt). Combinations of salmeterol and fluticasone propionate orbeclomethasone dipropionate, or salbutamol and fluticasone propionate orbeclomethasone dipropionate are preferred, especially salmeterolxinafoate and fluticasone propionate or salbutamol and beclomethasonedipropionate.

[0019] The formulations of the invention may be prepared by dispersal ofthe medicament in the selected propellant in an appropriate container,e.g. with the aid of sonication. The process is desirably carried outunder anhydrous conditions to obviate any adverse effects of moisture onsuspension stability.

[0020] The formulations according to the invention form weaklyflocculated suspensions on standing but, surprisingly, these suspensionshave been found to be easily redispersed by mild agitation to providesuspensions with excellent delivery characteristics suitable for use inpressurised inhalers, even after prolonged storage. Minimising andpreferably avoiding the use of formulation excipients e.g. surfactants,cosolvents etc in the aerosol formulations according to the invention isalso advantageous since the formulations may be substantially taste andodour free, less irritant and less toxic than conventional formulations.

[0021] The chemical and physical stability and the pharmaceuticalacceptability of the aerosol formulations according to the invention maybe determined by techniques well known to those skilled in the art.Thus, for example, the chemical stability of the components may bedetermined by HPLC assay, for example, after prolonged storage of theproduct. Physical stability data may be gained from other conventionalanalytical techniques such as, for example, by leak testing, by valvedelivery assay (average shot weights per actuation), by dosereproducibility assay (active ingredient per actuation) and spraydistribution analysis.

[0022] The particle size distribution of the aerosol formulationsaccording to the invention is particularly impressive and may bemeasured by conventional techniques, for example by cascade impaction orby the “Twin Impinger” analytical process. As used herein reference tothe “Twin Impinger” assay means “Determination of the deposition of theemitted dose in pressurised inhalations using apparatus A” as defined inBritish Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Suchtechniques enable the “respirable fraction” of the aerosol formulationsto be calculated. As used herein reference to “respirable fraction”means the amount of active ingredient collected in the lower impingementchamber per actuation expressed as a percentage of the total. amount ofactive ingredient delivered per actuation using the twin impinger methoddescribed above. The formulations according to the invention have beenfound to have a respirable fraction of 20% or more by weight of themedicament, preferably 25 to 70%, for example 30 to 60%

[0023] Optionally, the medicament may be surface-modified prior to itsdispersion in the propellant by treatment with a substantially non-polarliquid medium which is a non-solvent for the medicament. There is thusprovided in a further aspect of the invention an aerosol formulationcomprising particulate, surface-modified medicament, as defined herein,and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant,which formulation is substantially free of surfactant. By“surface-modified medicament” is meant particles of medicament selectedfrom the group consisting of salmeterol, salbutamol, fluticasonepropionate, beclomethasone dipropionate and physiologically acceptablesalts and solvates thereof which have been surface-modified by admixturewith a substantially non-polar non-solvent liquid, followed by removalof the liquid. The substantially non-polar non-solvent liquid medium isconveniently an aliphatic hydrocarbon, e.g. a lower alkane, which issufficiently volatile to permit its ready evaporation, e.g. at ambienttemperature and pressure, after slurrying with the medicament. The useof isopentane as liquid medium is particularly advantageous in thisrespect.

[0024] The medicament is desirably slurried with the liquid medium underanhydrous conditions to obviate any adverse effects of moisture onsuspension stability. The slurry may advantageously be sonicated tomaximise the surface-modifying effect of the treatment. The liquid maybe removed by any convenient means for example by evaporation or byfiltration followed by evaporation, provided that following treatmentthe medicament is substantially free of the liquid. The formulations ofthe invention will be substantially free of the non-solvent non-polarliquid. Surface-modified medicament prepared by the above-describedprocess comprises a further aspect of the present invention.

[0025] The formulations according to the invention may be filled intocanisters suitable for delivering pharmaceutical aerosol formulations.Canisters generally comprise a container capable of withstanding thevapour pressure of the propellant used such as a plastic orplastic-coated glass bottle or preferably a metal can, for example analuminium can which may optionally be anodised, lacquer-coated and/orplastic-coated, which container is closed with a metering valve. Themetering valves are designed to deliver a metered amount of theformulation per actuation and incorporate a gasket to prevent leakage ofpropellant through the valve. The gasket may comprise any suitableelastomeric material such as for example low density polyethylene,chlorobutyl, black and white butadiene-acrylonitrile rubbers, butylrubber and neoprene. Suitable valves are commercially available frommanufacturers well known in the aerosol industry, for example, fromValois, France (e.g. DF10, DF30, DF60), Bespak plc, UK (e.g. BK300,BK356) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser™).

[0026] Conventional bulk manufacturing methods and machinery well knownto those skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto an aluminium canto form an empty canister. The particulate medicament is, added to acharge vessel and liquified propellant is pressure filled through thecharge vessel into a manufacturing vessel. The drug suspension is mixedbefore recirculation to a filling machine and an aliquot of the drugsuspension is then filled through the metering valve into the canister.Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

[0027] Each filled canister is conveniently fitted into a suitablechannelling device prior to use to form a metered dose inhaler foradministration of the medicament into the lungs or nasal cavity of apatient Suitable channelling devices comprise for example a valveactuator and a cylindrical or cone-like passage through which medicamentmay be delivered from the filled canister via the metering valve to thenose or mouth of a patient e.g. a mouthpiece actuator. Metered doseinhalers are designed to deliver a fixed unit dosage of medicament peractuation or “puff”, for example in the range of 10 to 5000 microgrammedicament per puff.

[0028] Administration of medicament may be indicated for the treatmentof mild, moderate of severe acute or chronic symptoms or forprophylactic treatment. It will be appreciated that the precise doseadministered will depend on the age and condition of the patient, theparticular particulate medicament used and the frequency ofadministration and will ultimately be at the discretion of the attendantphysician. When combinations of medicaments are employed the dose ofeach component of the combination will in general be that employed foreach component when used alone. Typically, administration may be one ormore times, for example from 1 to 8 times per day, giving for example 1,2, 3 or 4 puffs each time.

[0029] Suitable daily doses, may be, for example in the range 50 to 200microgram of salmeterol, 100 to 1000 microgram of salbutamol, 50 to 2000microgram of fluticasone propionate or 100 to 2000 microgram ofbeclomethasone dipropionate, depending on the severity of the disease.

[0030] Thus, for example, each valve actuation may deliver 25 microgramsalmeterol, 100 microgram salbutamol, 25, 50, 125 or 250 microgramfluticasone propionate or 50, 100, 200 or 250 microgram beclomethasonedipropionate. Typically each filled canister for use in a metered doseinhaler contains 100, 160 or 240 metered doses or puffs of medicament.

[0031] The filled canisters and metered dose inhalers described hereincomprise further aspects of the present invention.

[0032] A still further aspect of the present invention comprises amethod of treating respiratory disorders such as, for example, asthma,which comprises administration by inhalation of an effective amount of aformulation as herein described.

[0033] The following non-limitative Examples serve to illustrate theinvention.

EXAMPLE 1

[0034] Micronised salmeterol xinafoate (24 mg) was weighed into a clean,dry, plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane (18.2 g)was added from a vacuum flask. The bottle was quickly sealed with ablank aluminium ferrule. The resulting aerosol contained 0.132% w/wsalmeterol xinafoate.

EXAMPLE 2

[0035] Micronised salmeterol xinafoate (38.28 g) and1,1,1,2-tetrafluoroethane (36.36 kg) were added to a pressure vessel andmixed with a high shear mixer for 20 minutes. Aliquots (18.2 g) of thesuspension were filled into aluminium cans closed with a metering valve,filling under pressure through the valve using conventional fillingequipment. The resulting inhalers contained 9.57 mg salmeterol xinafoateand delivered 25 microgram salmeterol (39.9 microgram salt) peractuation.

EXAMPLE 3

[0036] Micronised fluticasone propionate (24 mg) was weighed into aclean, dry, plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane(18.2 g) was added from a vacuum flask. The bottle was quickly sealedwith a blank aluminium ferrule. The resulting aerosol contained 0.132%w/w fluticasone propionate.

EXAMPLES 4 AND 5

[0037] Micronised fluticasone propionate (66 mg or 6.6 mg) was weigheddirectly into each of 100 open aluminium cans and a metering valve wasthen crimped into place on each can 1,1,1,2-Tetrafluoroethane (18.2 g)was then added to each canister under pressure, through the valve, andeach filled canister shaken to disperse the drug. The resulting inhalerscontained 66 or 6.6 mg fluticasone propionate and delivered 250 or 25microgram fluticasone propionate per actuation (Examples 4 and 5respectively).

EXAMPLE 6

[0038] Micronised salbutamol (24 mg) was weighed into a clean, dry,plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane (18.2 g) wasadded from a vacuum flask. The bottle was quickly sealed with a blankaluminium ferrule. The resulting aerosol contained 0.132% w/wsalbutamol.

EXAMPLES 7 AND 8

[0039] Micronised salbutamol (24 mg or 48 mg) was weighed directly intoeach of 3 open aluminium cans. 1,1,1,2-Tetrafluoroethane (18.2 g) wasadded to each can from a vacuum flask and a metering valve was thencrimped into place. Each filled canister was then shaken in anultrasonic bath for 8 minutes. The resulting inhalers contained 24 mg or48 mg salbutamol and delivered 100 or 200 microgram salbutamol peractuation (Examples 7 and 8 respectively).

EXAMPLE 9

[0040] Micronised salbutamol sulphate (31.7 mg) was weighed into aclean, dry, plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane(18.2 g) was added from a vacuum flask. The bottle was quickly sealedwith a blank aluminium ferrule. The resulting aerosol contained 0.174%w/w salbutamol sulphate.

EXAMPLE 10

[0041] Micronised salbutamol sulphate (31.7 mg) was weighed directlyinto each of 4 open aluminium cans. 1,1,1,2-Tetrafluoroethane (18.2 g)was added to each can from a vacuum flask and a metering valve was thencrimped into place. Each filled canister was then shaken in anultrasonic bath for 5 minutes. The resulting inhalers contained 31.7 mgsalbutamol sulphate and delivered 100 microgram salbutamol peractuation.

EXAMPLE 11

[0042] Isopentane (25 ml) was added to micronised salmeterol xinafoate(0.5 g) to form a slurry, which was sonicated for 3 minutes. Theresulting suspension was dried by evaporating the isopentane at ambienttemperature to yield surface-modified salmeterol xinafoate. Samples ofthis product (11.6 mg) were weighed into aluminium aerosol cans and1,1,1,2-tetrafluoroethane (18.2 g-99.95% w/w of total fill weight) wasadded to each can, whereafter suitable metering valves were crimped ontothe cans, which were then each sonicated for 5 minutes. The resultingaerosols contained salmeterol in an amount equivalent to 240 actuationsat 25 microgram per actuation.

EXAMPLE 12

[0043] Micronised beclomethasone dipropionate monohydrate (68 mg) wasweighed into a clean, dry, plastic-coated glass bottle and1,1,1,2-tetrafluoroethane (to 18.2 g) was added from a vacuum flask. Thebottle was quickly sealed with a metering valve. The resulting aerosoldispensed 250 microgram beclomethasone dipropionate (as the monohydrate)per 75.8 mg actuation.

EXAMPLE 13

[0044] Micronised salmeterol xinafoate (9.57 mg) is weighed directlyinto an aluminium can and 1,1,1,2,3,3,3-heptafluoro-n-propane (to 21.4g) added from a vacuum flask. A metering valve is crimped into place andthe filled canister sonicated for five minutes. The aerosol delivers 25microgram salmeterol per actuation.

EXAMPLE 14

[0045] Micronised fluticasone propionate (13.3 mg) is weighed directlyinto an aluminium can and 1,1,1,2,3,3,3-heptafluoro-propane (to 21.4 g)added from a vacuum flask. A metering valve is crimped into place andthe filled canister sonicated for five minutes. The aerosol delivers 50microgram fluticasone propionate per actuation.

EXAMPLE 15

[0046] Micronised salbutamol sulphate (29 mg) was weighed directly intoan aluminium can and 1,1,1,2,3,3,3-heptafluoro-n-propane (to 21.4 g)added from a vacuum flask. A metering valve was crimped into place andthe filled canister sonicated for five minutes. The aerosol delivered100 microgram salbutamol per actuation.

EXAMPLE 16

[0047] Micronised beclomethasone diproprionate monohydrate (62 mg) wasweighed directly into an aluminium can and1,1,1,2,3,3,3-heptafluoro-n-propane (to 21.4 g) added from a vacuumflask. A metering valve was crimped into place and the filled canistersonicated for five minutes. The aerosol delivered 250 microgrambeclomethasone diproprionate per actuation.

EXAMPLE 17

[0048] Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25microgram Fluticasone propionate 0.066 50 microgram1,1,1,2-Tetrafluoroethane to 100 to 75.8 mg

[0049] Micronised medicaments were weighed into an aluminium can,1,1,1,2-tetrafluoroethane (18.2 g) was added from a vacuum flask and ametering valve was crimped into place.

EXAMPLE 18

[0050] Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25microgram Fluticasone propionate 0.165 125 microgram1,1,1,2-Tetrafluoroethane to 100 to 75.8 mg

[0051] Micronised medicaments were weighed into an aluminium can,1,1,1,2-tetrafluoroethane (18.2 g) was added from a vaccum flask and ametering valve was crimped into place.

EXAMPLE 19

[0052] Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25microgram Fluticasone propionate 0.132 100 microgram1,1,1,2-Tetrafluoroethane to 100 to 75.8 mg

EXAMPLE 20

[0053] Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25microgram Fluticasone propionate 0.330 250 microgram1,1,1,2-Tetrafluoroethane to 100 to 75.8 mg

EXAMPLE 21

[0054] Per Inhaler % w/w Per Actuation Salbutamol* 0.132 100 microgramFluticasone propionate 0.132 100 microgram 1,1,1,2-Tetrafluoroethane to100 to 75.8 mg

EXAMPLE 22

[0055] Per Inhaler % w/w Per Actuation Salbutamol* 0.264 200 microgramFluticasone propionate 0.330 250 microgram 1,1,1,2-Tetrafluoroethane to100 to 75.8 mg

EXAMPLE 23

[0056] Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25microgram Beclomethasone dipropionate 0.066 50 microgram1,1,1,2-Tetrafluoroethane to 100 to 75.8 mg

EXAMPLE 24

[0057] Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25microgram Fluticasone propionate 0.264 200 microgram1,1,1,2-Tetrafluoroethane to 100 to 75.8 mg

EXAMPLE 25

[0058] Per Inhaler % w/w Per Actuation Salbutamol* 0.132 100 microgramBeclomethasone dipropionate 0.066 50 microgram 1,1,1,2-Tetrafluoroethaneto 100 to 75.8 mg

EXAMPLE 26

[0059] Per Inhaler % w/w Per Actuation Salbutamol* 0.264 200 microgramBeclomethasone dipropionate 0.264 200 microgram1,1,1,2-Tetrafluoroethane to 100 to 75.8 mg

[0060] In Examples 19 to 26 micronised medicaments are weighed intoaluminium cans, 1,1,1,2-tetrafluoroethane (18.2 g) is added from avacuum flask, and metering valves are crimped into place.

We claim:
 1. A pharmaceutical aerosol formulation which comprises aphysiologically effective amount of particulate salbutamol or aphysiologically acceptable salt or solvate thereof and1,1,1,2-tetrafluoroethane as propellant, which formulation issubstantially free of surfactant, with the proviso that when saidformulation consists essentially of salbutamol or salbutamol sulphateand 1,1,1,2-tetrafluoroethane the weight to weight ratio of medicamentto propellant is other than 69:7900 (0.866%).
 2. A pharmaceuticalaerosol formulation which comprises a physiologically effective amountof particulate salbutamol or a physiologically acceptable salt orsolvate thereof and 1,1,1,2-tetrafluoroethane as propellant, whichformulation is substantially free of surfactant, with the provisos thatwhen said formulation consists essentially of salbutamol and1,1,1,2-tetrafluoroethane in a weight ratio of 0.05:18, said salbutamolis present in the form of a physiologically acceptable salt and whensaid formulation consists essentially of salbutamol or salbutamolsulphate and 1,1,1,2-tetrafluoroethane the weight to weight ratio ofmedicament to propellant is other than 69:7900 (0.866%).
 3. Apharmaceutical aerosol formulation consisting essentially of aphysiologically effective amount of particulate salbutamol or aphysiologically acceptable salt or solvate thereof and1,1,1,2-tetrafluoroethane as propellant, with the proviso that when saidformulation consists essentially of salbutamol or salbutamol sulphateand 1,1,1,2-tetrafluoroethane the weight to weight ratio of medicamentto propellant is other than 69:7900 (0.866%).
 4. A pharmaceuticalaerosol formulation which comprises a physiologically effective amountof particulate salbutamol or a physiologically acceptable salt orsolvate thereof and 1,1,1,2-tetrafluoroethane as propellant, whichformulation is substantially free of surfactant, and wherein thesalbutamol or a physiologically acceptable salt or solvate thereof ispresent in an amount of less than 0.866% w/w based on the total weightof the formulation.
 5. A pharmaceutical aerosol formulation whichcomprises a physiologically effective amount of particulate salbutamolor a physiologically acceptable salt or solvate thereof and1,1,1,2-tetrafluoroethane as propellant, which formulation issubstantially free of surfactant, and wherein the salbutamol or aphysiologically acceptable salt or solvate thereof is present in anamount of 0.005 to 0.594% w/w based on the total weight of theformulation.
 6. A pharmaceutical aerosol formulation which comprises aphysiologically effective amount of particulate salbutamol or aphysiologically acceptable salt or solvate thereof and1,1,1,2-tetrafluoroethane as propellant, which formulation issubstantially free of surfactant, and wherein the salbutamol or aphysiologically acceptable salt or solvate thereof is present in anamount of 0.005 to 0.264% w/w based on the total weight of theformulation.
 7. A pharmaceutical aerosol formulation which comprises aphysiologically effective amount of particulate salbutamol or aphysiologically acceptable salt or solvate thereof and1,1,1,2-tetrafluoroethane as propellant, which formulation issubstantially free of surfactant, and wherein the salbutamol or aphysiologically acceptable salt or solvate thereof is present in anamount of 0.005 to 0.174% w/w based on the total weight of theformulation.
 8. A pharmaceutical aerosol formulation which comprises aphysiological effective amount of particulate salbutamol or aphysiologically acceptable salt or solvate thereof and1,1,1,2-tetrafluoroethane as propellant, which formulation issubstantially free of surfactant, and wherein the weight ratio ofsalbutamol or a pharmaceutically acceptable salt or solvate thereof topropellant is less than 0.05:18.
 9. A formulation as claimed in any oneof claims 1 to 8 wherein the medicament is salbutamol sulphate.
 10. Aformulation as claimed in any one of claims 1 to 8 which containssalbutamol or a physiologically acceptable salt or solvate thereof incombination with an anti-inflammatory steroid or an anti-allergic.
 11. Aformulation as claimed in any one of claims 1 to 8 which containssalbutamol or a physiologically acceptable salt or solvate thereof incombination with fluticasone propionate or beclomethasone dipropionateor a physiologically acceptable solvate thereof.
 12. A formulation asclaimed in any one of claims 1 to 8 which contains salbutamol andbeclomethasone dipropionate.
 13. A formulation as claimed in any one ofclaims 1 to 8 which has a respirable fraction of 20% or more by weightof the salbutamol or a physiologically acceptable salt or solvatethereof.
 14. A canister suitable for delivering a pharmaceutical aerosolformulation which comprises a container capable of withstanding thevapour pressure of the propellant used, which container is closed with ametering valve and contains a pharmaceutical aerosol formulation whichcomprises a physiologically effective amount of particulate salbutamolor a physiologically acceptable salt or solvate thereof and1,1,1,2-tetrafluoroethane as propellant, which formulation issubstantially free of surfactant and with the proviso that when saidformulation consists essentially of salbutamol or salbutamol sulphateand 1,1,1,2-tetrafluoroethane the weight to weight ratio of medicamentto propellant is other than 69:7900 (0.866%).
 15. A canister as claimedin claim 14 wherein the container is a metal can.
 16. A metered doseinhaler which comprises a canister as claimed in claim 14 fitted into asuitable channelling device.
 17. A method of treating respiratorydisorders which comprises administration by inhalation of an effectiveamount of a pharmaceutical aerosol formulation which comprisesparticulate salbutamol or a physiologically acceptable salt or solvatethereof and 1,1,1,2-tetrafluoroethane as propellant, which formulationis substantially free of surfactant.